The pedunculopontine nucleus (PPN) helps control
sleep-wake rhythms and modulates posture and locomotion. The proposed research
will address three functional aspects (ascending, local and descending) of the
PPN, the cholinergic arm of the Reticular Activating System (RAS). From 10-30
days postnatally there is a dramatic decrease in the percent of REM sleep in the
rat. A hypothesis was proposed suggesting that disturbances in the developmental
decrease in REM sleep, a return to a neonatal state of REM sleep drive, could
lead to a number of disorders characterized by increased REM sleep drive. We
tracked changes in ascending and descending projections from the PPN, along with
developmental changes in neurochemical systems modulating the PPN. We found that
certain neurotransmitters could be responsible for modulating the developmental
decrease in REM sleep, reported new interactions between identified cell types,
and proposed a push-pull model for PPN modulation of posture and locomotion. We
also discovered the presence of electrical coupling in the PPN as well as in an
ascending and a descending target of the PPN. Preliminary evidence suggests that
changes in electrical coupling parallel the developmental decrease in REM sleep.
This newly discovered mechanism will be explored using a) whole-cell patch clamp
and intracellular sharp electrode recordings, b) pharmacological manipulation to
induce and block electrical coupling, and c) measures of connexin-36 mRNA
expression and protein levels before and during the developmental decrease in
REM sleep (7-30 days), in 1) the parafascicular nucleus (Pf), an ascending
target of the PPN, 2) the PPN itself, and 3) the SubCoeruleus (SubC) nucleus, a
descending target of the PPN implicated in the generation of REM sleep. The
discovery of electrical coupling in these RAS nuclei is critical given that
recent findings suggest that the stimulant modafinil exercises its effects by
increasing electrical coupling. Conversely, a number of anesthetics are known to
decrease electrical coupling. The mechanistic characterization proposed
represents a new paradigm for sleep-wake control and may revolutionize how we
think about sleep-wake control, reveal how electrical coupling interacts with
known transmitter inputs in the RAS to modulate sleep-wake states, and how we
may develop new therapeutic strategies for the treatment of a number of
devastating disorders that have as a common symptom the manifestation of
increased REM sleep drive. In fact, by ignoring the role of electrical coupling
we will fail to understand this system. We discovered the presence of electrical
coupling, by which nerve cells can communicate directly through pores called gap
junctions, in the part of the brain that controls sleep-wake cycles, the
reticular activating system (RAS). We demonstrated the presence of electrical
coupling using recordings from pairs of neurons. This finding helps explain the
actions of some anesthetics, which are known to block gap junctions, and of a
new stimulant, modafinil, which is now known to increase electrical coupling.
This novel mechanism may promote ensemble activity in large numbers of neurons
to promote rhythms during waking, and the absence of such activity may lead to
sleep. We propose a series of detailed studies to investigate the organization
(which cells are coupled, which are not), the control (which transmitter systems
activate, which inhibit), and the modulation (which agents can increase vs
decrease coupling) of this mechanism. The mechanistic characterization proposed
represents a new paradigm for sleep-wake control and may revolutionize how we
think about sleep-wake control, reveal how electrical coupling interacts with
known transmitter inputs in the RAS to modulate sleep-wake states, and how we
may develop new therapeutic strategies for the treatment of a number of
devastating disorders that have as a common symptom the manifestation of
increased REM sleep drive. In fact, by ignoring the role of electrical coupling
we will fail to understand this system.